Prostaglandin E2 (PGE2) has been known as a metabolite in the arachidonic acid cascade. It has been known that PGE2 possesses cyto-protective activity, uterine contractile activity, a pain-inducing effect, a promoting effect on digestive peristalsis, an awaking effect, a suppressive effect on gastric acid secretion, hypotensive activity, and diuretic activity.
In the recent study, it was found that PGE2 receptor was divided into some subtypes, which possesses different physical roles from each other. At present, four receptor subtypes are known and they are called EP1, EP2, EP3 and EP4 respectively [J. Lipid Mediators Cell Signaling, 12, 379-391 (1995)].
Among these subtypes, EP3 receptor was believed to be involved in signal transduction of peripheral nerve, control of exothermal reaction in central nerve, formation of memory by expressing in cerebral neuron, vascularization, and reabsorption of urine by expressing in renal tubular, uterine contraction, production of ACTH, platelet aggregation. Besides, it was expressed in vascular smooth muscle, heart and gastrointestinal tract also.
Therefore, the compounds that can bind to EP3 receptor strongly and show the antagonizing activity are useful for the prevention and/or treatment of diseases induced by excess activation of EP3 receptor.
As a compound possessing EP3 and/or EP4 receptor antagonist activity, in a specification of WO 02/16311, a carboxylic acid compound of formula (IA):
wherein R1A is COOH, COOR6A; R6A is C1-6 alkyl etc.; AA is C1-6 alkylene etc.; R2A is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, halogen atom, CF3, cyano, nitro, hydroxyl, NR11AR12A, CONR11AR12A, SO2NR11AR12A, or —S(O)XA—(C1-6)alkyl; mA is 0, 1, or 2; R11A and R12A each independently, is hydrogen or C1-4 alkyl; XA is 0, 1 or 2; BA ring is C5-7 membered mono-carbocyclic ring; R3A is hydrogen or C1-4 alkyl; R4A is C1-8 alkyl, C2-8 alkenyl; R5A is C5-10 mono- or bi-carbocyclic ring or 5-10 membered mono- or bi-heterocyclic ring including at least of hetero atoms selected from nitrogen, oxygen or sulfur, which each ring was substituted with 1-2 of R13A or unsubstituted; R13A is C1-6 alkyl, C1-6 alkoxy, halogen atom, CF3, cyano, C1-4 alkoxy(C1-4)alkyl, phenyl, phenyl(C1-6)alkyl, —(C1-4 alkylene)yA-J-(C1-8 alkylene)ZA-R14A, benzoyl, or thiophenecarbonyl; or a non-toxic salt thereof, are described.